OMICS INVESTIGATION OF NEURODEVELOPMENT IN MOUSE MODELS OF AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects neuronal populations of the motor cortex (MC) and spinal cord (SC), leading to rapidly progressing paralysis and death within two to five years after symptom onset. While most ALS cases are considered sporadic, approximately 10% are familial, with causative mutations identified in over half of these cases, the most represented being C9orf72, SOD1, TARDBP and FUS. Like other neurodegenerative diseases, ALS is a typical late-onset disease, which suggests that it only hits the adult and mature central nervous system. However, accumulating evidence suggest that genetic cases might arise from infra clinical neurodevelopmental impairment. These would be quickly and efficiently compensated by the developing central nervous system, preventing the emergence of typical neurodevelopmental symptoms, until compensatory mechanisms weaken, leading to late disease onset. To test this hypothesis, my PhD project aims at investigating the early molecular alterations in two genetically and phenotypically complementary mouse models of ALS: Sod1^G86R and Fus^ΔNLS/+. Both the MC and the SC from P0 animals are being investigated at the transcriptomic (snRNA-seq) and proteomic (LC-MS) levels. This integrative approach aims to identify initially impaired neurodevelopmental pathways that might be either common, or specific to Sod1^G86R or Fus^ΔNLS/+ mouse models of ALS. Transcriptomic and proteomic data of the MC samples have been generated and are currently under analysis. Altogether, this project may not only inform on developmental ALS-related molecular alterations and novel therapeutic targets, but may also contribute to shifting the perspective of the origin of ALS.